Concomitant tumor immunity is the response whereby a host with a progressive tumor rejects an inoculum of the same tumor at a distal site. This tumor-primed, T cell-mediated protection was previously thought to occur only with highly-immunogenic tumors. However, we have recently found that concomitant immunity to poorly-immunogenic tumors can be induced by the depletion of regulatory T cells (Tregs). The proposed studies will characterize the mechanisms that govern the induction, maintenance, and suppression of concomitant immunity. This research will employ a poorly-immunogenic mouse melanoma model that closely resembles human disease. This proposal will test the hypothesis that progressive, poorly-immunogenic tumors have the capacity to instruct durable immunity to cancer. Specific Aim 1 will identify mechanisms for the maintenance of concomitant immunity following the surgical excision of primary tumors. Studies will characterize long-term post-excisional protection against local and metastatic melanoma. Protection will be correlated with the tumor-induced priming of central and effector memory T cell responses against multiple melanoma-expressed self antigens. Specific Aim 2 will define the mechanisms whereby optimum concomitant immunity is induced. The stimulation of various T cell populations through GITR (glucocorticoid-induced TNFR family-related protein), as well as the administration of lymphodepleting chemotherapy will be investigated as methods for driving activation and proliferation of CD8+ effector and CD4+ helper T cells in tumor-bearing hosts. By monitoring concomitant immunity, these studies will reveal the generation of protective immune responses that would otherwise remain undetected in tumor-bearing hosts. Specific Aim 3 will define mechanisms whereby tumors suppress concomitant immunity. Studies will rely on transgenic mice expressing a Foxp3-GFP reporter gene to enable the precise characterization of Tregs in tumor-bearing mice. Results are expected to demonstrate that progressive, poorly-immunogenic melanoma induces priming and expansion of Tregs that are specific for tumor-expressed self antigens. Collectively, the proposed studies will define mechanisms for generating durable, T cell-mediated immunity in hosts bearing poorly-immunogenic tumors, without the use of active immunization (vaccines). These studies are expected to demonstrate that manipulating the host's own immune milieu during tumor growth is sufficient for inducing long-lived protection against recurrent and metastatic disease. Surgery is currently the most successful treatment for solid tumors. However, patients continue to succumb to metastatic disease. This research is expected to lead to therapies which will utilize patients'own immune systems to prevent the recurrence and metastasis of cancers following surgery.